This is a pioneering article on the use of buspirone use in anger and irritability in adults.

Based on the data available, buspirone appears an extremely safe medication in adults. Of course, all patients should be evaluated by a physician. We gratefully acknowledge the opportunity to publish a minor adaptationof this article which originally appeared in the Australian Journal of Psychopharmacology in 2003. This articlewas published in the Australian J of Psychopharmacology—the final draft may not necessarily be identical.

Vernon M Neppe

Evidence
exists for serotonin and specifically the 1A receptor involvement in the
aggression spectrum using animal and human models. High dose beta
2-adrenergic blockers, lithium and eltoprazine all act non-specifically on
serotonin 1A and are apparently anti-aggressive.

Animal models of aggressionsuggest the azapirones are potent
anti-aggressive agents hypothetically through its specific serotonin
1Apartial agonist effects. Irritability is an early target symptom
of response with buspirone in generalized anxiety disorder and scattered
case reports suggest and anti-aggressive effect for buspirone.

4 clinical open study cohorts using buspirone in
aggression are described: Experience suggests a biphasic dose effect for buspirone : Low doses of buspirone ( 15-25 mg per day )
were effective after a few days in alleviating irritability (N=9
inpatients) without associated significant anxiety. Higher doses such as
60-90 mg per daywithin a day greatly relieved manic irritability,agitation,restlessness and mood lability in 12 in-
and out-patients. Two cohorts of outpatients (thirteen without coarse
organicity and twenty (initially. later twelve) with carbamazepine adjunct)
showed impressive results generally over a prolonged period(18/18
{15-25mg buspirone daily}, 3/3 {30-45mg}, 9-10/12 {≥60mg}. Eight
stopped the carbamazepine.

There are major limitations to this study including
selected sample, retrospective review, rankings,milieu, patient motivation,
assessment methods, clinical presentations and polytherapy but the results
are encouraging and require adequate controlled studies. If real,these effects
can be explained in a unified serotonin 1 A pre- and post-synaptic theory.

AGGRESSION

Concept of Aggression

There is no current diagnostic
framework for aggression.The
Diagnostic and Statistical Manual III Revisionand DSM-IV and 1V-R1, 2,recognizes a variety of different syndrome criteria,making up subgroups of psychosis,anxiety and depression.However,the fourth potential system
cluster in that quartet,aggression,is represented
only by the condition of intermittent explosive disorder(IED).IED is limiting in that one cannot diagnose it in the face of a
major contribution from common diagnostic conditions such as depression,substance
use,anxiety and psychosis and
mania. Moreover,the aggressive episodes are not better accounted for by another
mental disorder (e.g.,Antisocial Personality Disorder,Borderline Personality Disorder,Head injury,Alzheimer’s
disease,Conduct Disorder,or Attention-Deficit / Hyperactivity
Disorder) and are not due to the direct physiological effects of a
substance (e.g. a drug of abuse or
a medication) or a general medical condition (e.g.,head trauma or Alzheimer's
disease). In DSM 111 Rit implied phases of normality
between episodes,something which is
almost contradictory to the condition,and fortunately this has been eliminated in DSM 1V. Nevertheless,it remains a
rare condition,requiring
disproportionate dyscontrol. 2

Empirically,by far the most common form of
aggression relates to frustration leading to outbursts of anger : many of
these people have mainly controlled aggression directed towards others
without amnesia of any kind,and may
be experiencing a relatively chronic high basal level of stress.Thus,one could argue that there are two
dichotomous poles in relation to aggression,what Dieter Blumer and Ihave called “paroxysmal behavioral
disorder” 3,4-the
explosive loss of control disorder possibly associated with firing in the
brainpossibly in relation to
epilepsy-related behavioral changes 5and the
frustration -aggression component which is chemically linked to
norepinephrine and serotonin but has no overt organic (coarse
neurobehavioral ) elements..
Aggression is by its nature episodic : Even if
those episodic elements persist almost continuously over time,they are perceived as chronic episodic
elements. Even planned aggressive elements have episodic expression.

A
further complicating elementrelates to terminology.In aggressionresearch we come across a variety
of terms which if not synonymous are very similar.Rageis used to imply profound
outbursts of anger which are not controlled.In the medical context, this frequently implies acoarse neurobehavioral componentwith high levels of aggression.Dyscontrolis similar but has an impulsive
component to it,with elements of
loss of control,non-directedness,and,at times,amnesia.Anger implies
outbursts which are under control,which are generally directed,and usually have verbal components or
components expressing themselves somatically. Irritabilityis generally used to imply high
basal levels of anger and agitation - a simmering over time. Hostilityis
further along this continuum,in
that it does not necessarily even imply the expression of anger:
passive-aggressive components inhostility may be state or trait related. Violenceis perceived as physical force
exerted for the purpose of violating,damaging,or abusing implying
elements of some premeditation.Even
assertivenesshas
elements of aggression which are perceived as socially appropriate. Finally,impulsivityrelates to many of the above,because of the inherent nature of
aggressive behavior having episodic elements but impulsivity goes beyond
aggression alone. Moreover,impulsivity also relates to any
kind of symptom,so that it will
include such a major phenomenon as episodic labilityas well. It also covers behavior which is
non-motivated,not
well thought out and acted out generally to the detriment of the patient.
These variations in terminology reflect one of the difficulties of
quantifying aggression. Operationally,probably the easiest measure of
entry into pathologic aggression research is the recognition that the anger
is impairing functioning at any of the biopsychofamiliosociocultural
levels. Given the lack of aggression classification in

in
the Diagnostic and Statistical Manual III revision or DSM-IV,there are no FDA approved drugs for
aggression.Thus
all drug discussion is necessarily Innovative Psychopharmacotherapy.This is a cogent reason for developing a
classification intoDSM V and Figure 1 represents my preliminaryproposal presented without further
comments.

Aggression and irritability are
extremely difficult to measure. A variety of different scales have been
developed,some
relating to patient subjective rankings,others to objective rankings by researchers.Subjective rankings such as the
Buss-Durkee,Monroe Dyscontrol Scales,SpielbergerState and Trait
Aggression Scales,and a variety of
Short Aggression Questionnaires,have value in apopulation
that is cooperative,motivated,non-psychotic and of normal intelligence.However,subjective rankings cannot easily
be used in a psychotic or demented population,both of whom,at times,have complications pertaining to aggression and irritability.

Objective
rating scales have the advantage of being quantifiable.The earliest modern one of these is the
Yudofsky Overt Aggression Scale 6 which however is nominal and not ordinal,and evaluates
outbursts of verbal and physical aggression.This wasmade ordinal by Kay's
modification,The Modified Overt
Aggression Scale 7.In
practice,these
scales are difficult to use because patients in an inpatient situation will
commonly not exhibit episodes of aggression.Monitoring episodes of aggression is
difficult and measurement is problematic in practice. 6,7,8, 9. If the patient is an inpatient,he is not under the same kind of
stressors 10 and is less likely to have anger outbursts.

Consequently,measures of hostility such as
those found in the Brief Psychiatric Rating Scale 11 and quantified by Kay12,
13, 14,may be
useful at this point,and in fact
has been used in Cohort 1 of the research below. Additionally,monitoring
specific episodes allows the patient or members of family to monitor
outpatient aggression. This I have found has been most suitable,and the patient
or responsible other generally monitors episodes such that instrument
sensitivity becomes adequate.

THE BIOCHEMICAL LINKS

Chemistry: The role of serotonin

Serotonin,chemically 5
hydroxy tryptamine (5HT),was
isolated in platelets in 1947,almost a century after its initial discovery as a substance that
contracted smooth muscle.The
serotonin receptors apparently modulate a variety of basic functions at a
large number of levels. Serotonin has physiologic effects on the
hypothalamo-pituitary axis impacting neuroendocrine functions and circadian
rhythms,and
it regulates temperature and even blood pressure. It has psychologicaleffects on memory,irritability,stress,mood lability,anxiety,depression and obsessionality. It
alsohas behavioral effects on
sleep,sex,appetite and weight and itmodulates aggression 15, 16, 17, 18,19, 20

The
serotonin syndrome is a syndrome of serotonin overload in experimental
animals associated with a variety of hyperactivity features. [19, 21 A significant pharmacologic measure,namely partial
agonism,can be demonstrated most
easily by inducing and blocking such a syndrome. Partial agonism implies
that in the presence of an agonist these drugs,by occupying the receptor,act as functional antagonists. However,in the absence
of agonists,there will be no
functional antagonism.In contrast,given an
adequate dose,there will be an
incomplete agonist action producing a weak serotonin syndrome.Partial agonism is a post-synaptic
phenomenon which can be perceived clinicallyas potentially
neuromodulatinga condition back to
normal. 22

Serotonin
receptorology,however,is complicated
by numerous different actions. Today,we know of at least fifteen
different serotonin receptor subtypes all with specific anatomy,physiology,pharmacology,receptor responsiveness and probably even
genetic predisposition based on cloning.*

The
promise of a breakthrough in brain receptorology led to the rapid
delineation of serotonin receptor subtypes,beginning in 1979 17. The 1980's saw the further subtyping of
receptors into types 1 and 2. 23, 24 The serotonin 3 receptor was a third class 25 then came serotonin 4 26,5,6 and 7 as well asseveral receptor subtypes like 1F 27 (Serotonin 1A in 1981 through to current
discoveries in 1995) 28, 29

Serotoninand aggression

There is substantial research suggesting a link of
aggression and serotonin. 20, 30, 31, 32, 33, 34,
35, 36, 37, 38, 39, 40, 41, 42, 43 For example,in several studies of aggression,the CSF5-hydroxy-indole
acetic acid level is inversely related to the extent of aggression. 44 As 5-HIAA is a metabolite of serotonin,and deficiency
would imply possible serotonin two excess states with long term down
regulation,this result may have
some relevance. Animal models support this :
decreased serotonergic activity increases predatory behavior. 38, 40, 44, 45, 46

There are difficulties in
interpreting serotoninand aggression states. For example,fluoxetine,an inhibitor of serotonin uptake and
other serotonin-mimetics inhibit mouse killing behavior without apparent
secondary effects and when these compounds were tested on killer rats,a stronger antimuricidal effect was
observed in rats having altered serotonin neurotransmission. These results
support a role for the serotonergic supersensitivity in a model of
aggressive behavior. 40. Yet,in delta 9-Tetrahydrocannabinol
(THC) induced aggressive behavior in rats previously deprived of REM
sleep,aggressiveness was
significantly potentiated by tryptophan and fluoxetine. 42Further
complicating animal interpretations is the use of the overlapping paradigms
for aggression and anxiety. 20, 33, 36, 47,45

Serotonin 2 and aggression

Several drugs which have been
noted empirically but not in double blind studies to have anti-aggressive
effects act on the serotonin 2 receptor (now the 5-HT 2A Receptor subtype).
The phenothiazines and other neuroleptics may have 5 % to 30 % of their
total receptor profile as serotonin 2 blockade. 48,
49For many
years,phenothiazines were used as anti-agitation drugsand their effects in taming animals are
well-known. 50, 51, 52 Trazodone has serotonin 2 blocking effects and in
case reports has anti-aggressive effects. 53, 54, 55, 56, 57, 58,
59

The relevance of these
effects in the context of the data below is the apparent inverse control
with serotonin 1A drugs:1A agonism
seems to have similar effects or controlling effects to2A antagonism using several
pharmacologic models. 22, 60This is
also seen clinically with anti-aggressive,anti-anxiety and anti-depressant
parallels but not with other areas,some controversial,such as
sedation and psychosis with 5HT 2A not 1A,and anti-impulsivity aspects and neuroregulation with 1A not 2A.

Serotonin 1A receptors

The serotonin 1 receptors,particularly
serotonin 1A,are relevant in aggression.The serotonin 1A receptor was discovered
in the early 1980's,and serotonin 1 and then serotonin 1A was differentiated at
that point,relating to their
specific interactions with guanasyl nucleotides, adenylyl cyclaseand differential effects with
differentligands. 61, 62, 63, 64, 65, 66

Serotonin
1A has its own special serotonin syndrome 67, 68, . Both the azapirones
and the benzodioxines conform to the properties ofa partial agonist at the serotonin
1A level. 69, 70,.71, Partial agonists may imply a mechanism for
neuromodulation. These effects may have implications for high dose
(post-synaptic) effects such as possible anti-aggressive effects in high
threshold subpopulations such as mania. (hypothesized
in Cohorts 2,3 and 4 below ). The
functions of serotonin could reflect serotonin 1A neuromodulation as well
because serotonin 1A has remained unique amongst the serotonin receptor
subtypes as the action of drugs acting on this receptor is both presynaptic
directly at the raphe nucleus level and,in sufficient doses,post-synaptic at the hippocampus,amygdala,cerebral cortical
level 20, 72.Low doses
(presynaptic or autoreceptor level doses) of such compounds acting at this
level may also have implications for aggression (hypothesized in Cohorts 1,3 and 4 below).

Serotonin 1A Drugs

There are three groups of
drugs in which the serotonin 1A neuromodulation model can
be tested. The azapirone,buspirone (marketed for control of
anxiety and mixed anxiety-depression)is ideal because of its specificity for the serotonin 1A receptor at
therapeutic doses 20, 72-- its effects on the dopamine receptor in a
non-sensitized individual should occur only an order of magnitude
higher,say at doses of 300 or 400
mg per day,although electrically
firing at a dopaminergic cholinergic and noradrenergic levels occurs in
pharmacologic doses.20, 73, 74, 19, 75

This
theory can be tested using other examples based on
empirical data.

Lithium

Lithium
has been well demonstrated to have some degree of anti-aggressive effect 84, 85,but it islittle-known that lithium acts as a
post-synaptic serotonin 1A agonist in rodent models.83 Administration of lithium chloride for 3-14 days
enhances the components of the serotonin syndrome produced by
8-hydroxy-2-(di-propylamino)tetralin (8-OH-DPAT) in the rat,but the hypothermic response ( ?
presynaptic) was unaltered. By contrast,responses at the5-HT1B receptor agonist were unaltered by repeated lithium
administration 83. .

Beta-adrenergic blocking agents

The beta2 adrenergic blockerspredominantly antagonize the
serotonin 1A post-synaptic receptor but non-specifically.Beta1 and 2 adrenergic blockade makes
interpretation of which action is occurring more difficult.

There
are at least 11 marketed beta-blockers in various
countries of which eight are non-cardioselective - they act on the beta 2
receptor even in low doses. 86, 87. Of these,propranolol 70, 76, 77, 78, 88 andpindolol 64, 69, 77, 89 particularly have been evaluated with regard to
theirserotonin 1A post-synaptic receptor
action andalprenolol 79, 90, 91, 92, timolol 92, 93, oxprenalol 94, 95 and possibly nadolol 74 all been demonstrated to have serotonin 1A
antagonism effect. The link to serotonin 1A of the beta 2 -adrenergic
blocking agents was demonstrated definitively in 1988 when the genomic
clone of serotonin 1A was produced from an attempt to isolate the beta 2
adrenergic receptor which itresembles and is apparently part of 96, 97. The 5HT1A receptoractivity of the beta-blockers
maydepend onthe beta 2 -adrenergic effect :
d-propranolol,the dextroisomer of
propranolol is ineffective as a beta-adrenergic blocking agent 98, 99,and also
is an ineffective serotonin 1A antagonist. 100. This emphasizes how difficult it is to
differentiate beta 2 from serotonin 1A effects.

Clinically,beta blockers have been used in
low dosage to lower somatic symptoms of anxiety,and with it there is a lowering of
frustration with a lowering of aggression.This is probably an adrenergic,non-serotonin related
phenomenon,and frequently
corresponds empirically with a pulse in the high 60's. 86, 87A pulse in
the low 60's corresponds with high doses of lipid-soluble beta-adrenergic
blocking agents such as propranolol and pindolol,and these drugs in high doses have
been used in the control of rage and aggression,particularly organic rage.This seems anomalous because (-) Pindolol
and (-) propranolol displayed high affinity for 5-HT1A as potent
antagonists at 5-HT1A receptors in rat hippocampus 101.. Moreover,(-) propranolol
has certain impinging effects on the serotonin 2 receptor ( e.g. relatively high doses of propranolol
only partially antagonized the effects of LSD) 70. Consequently,this may imply
that serotonin 2 antagonism is not the mechanism linked to anti-aggressive
effects. However,like the
beta-adrenergic antagonist,pindolol,propranolol binds with high affinity to
5-HT1B 76, 102.Propranolol binds stereoselectively
both at 5-HT1A and 5-HT1B sites (with a several-fold selectivity for the
latter) and,whereas it is a 5-HT1A
antagonist,it appears to be a
5-HT1B agonist. As such,it could serve as a lead compound for the development of new
5-HT1A and 5-HT1B agents based on preliminary studiesfor the development of novel serotonergic
agents 103. . Moreover,some beta-adrenoceptor antagonists
may behave as mixed agonists-antagonists at the 5-HT autoreceptor. 104 .Finally,(-)-propranolol is a relatively
weak antagonist of 5-HT itself,suggesting that the endogenous neurotransmitter may have actions on
dorsal raphe neurons in addition to those mediated by 5-HT1A receptors. 88

However,a confounding factor is that beta
blockers such as propranolol also act in serotonin 1B as agonists. 76, 105, 106 The serotonin 1B
receptor has at this point not been demonstrated in man 106, 107,but many
of the more perplexing features relating to the anti-aggressive action of
beta blockers which may be 5HT 1A antagonists,may be explained on the basis of a
possible presence of serotonin 1B in man at which the beta blockers may be
agonists. (Neppe,1990) The
serotonin 1B receptor is a very potent anti-aggressive receptor,using the rodent
model. This may or may not be applicable in man because no serotonin 1B
receptor has thus far been demonstrated in
humans.Moreover,the effect potentially could still
be non-serotonin related and beta adrenergic,so that these are complicating hypotheses.These are needed
to explain what has been found clinically with propranolol and aggression.

The
use of high dose propranolol in rage and aggression is very promising.
Several studies of generally high doses of propranolol used for aggression
in organic brain syndromes in children,Korsakoff's psychosis,in schizophrenia,severe mental retardation,adult autismand chronic organic brain syndromes have
suggested its usage. 87, 108, 109, 110, 111 Real rage requires higherdoses of lipophilic drug and the effects
are delayed weeks with the pulse beingnot in the mid-sixties as for somatic anxiety but lower suggesting a
second different mechanism. Additionally,by contrast,low doses and theperipheral effects of several
beta-adrenergic blocking agents produce almost immediate relief ofaggression linked tofrustration 87Moreover,animal studies
support the anti-aggression effect of propranolol. 112Studies
with other lipid soluble beta 2 -adrenergic blocking agentssuch as pindololexist. 113 Some of the effects may well be beta-adrenergic
in higher doses or the serotonin mechanisms or combinations can be invoked. 87

Can
one reconcile these three groups of drugs in relation to the pharmacology
of aggression?Clearly,agonism at
serotonin 1A levelcould be
supported by buspirone and by lithium,but is apparently contradicted by propranolol. These studies
complement research in aggression with both the azapirones and lithium -
relevant because lithium has amongst other actions,serotonin 1A effects.

We
now review the literature on the more specific serotonin 1A compounds, the
azapirones.

The azapirones

The
exploration of serotonin 1A functions has had impetus with the development ofa series of
compounds,the azapirones,which appear specific for this receptor
in therapeutic doses. There are at least 11 azapirones being researched : These drugs differ from the benzodiazepines
structurally and also in that they have no significant effects on
seizures,have no muscle relaxant
effect and their anti-anxiety action is delayed for some two to three or
four weeks. 19, 114, 115 However,the only marketed one currently is
buspirone in which there is patient experience on several million. One can
measure the functional effects of buspirone because it can block the
serotonin 1A specificagonist effects of 8-hydroxy DPAT116, 117implying
some antagonist effects.But in high
enough doses,buspirone,and
particularly its azapirone analog,gepirone,can induce a
serotonin 1A related syndrome. 118, 119,117. This implies that functionally buspirone has
both serotonin agonist and serotonin antagonist effects leading to the
hypothesis of partial agonism. 117, 120, 121 Additionally,a great deal of firing has been
demonstrated at the presynaptic autoreceptorlevel in relation to serotonin 1A. This
firing occurs in the dorsal raphenucleus.When presynaptic agonism occurs, by virtue of
feedback loops,there will overall
beless serotonin available
post-synaptically for the synapse because ultimately there will be lowered
serotonin tone. 72,
118. This would imply
blockade not only at serotonin 1A levels,but serotonin 2 and possibly serotonin 3 levels with a functional
post-synaptic serotonin antagonism overall,including a serotonin 2 antagonism 60, 118, 122, 123. The azapirones act pre-synaptically as complete
agonists. This produces firing at that level with an overall endpoint
diminution in serotonergic tone post-synaptically. 60,
118 In the animal model this has been
well-demonstrated 117, although there may be some attenuation of this
post-synaptic serotonergic tone 124and
overall antagonism at serotonin 1,2 and possibly 3 levels.This mechanism may be very important in
using low doses of buspirone in aggression.

In high doses
buspirone acts as a moderate but incomplete serotonin 1A agonist.The differentiation of pre-synaptic and
post-synaptic effects has been argued to be appropriately modeled on such
features as pre-synaptic hypothermia and post-synaptic elevations of prolactin which can be blocked by serotonin antagonist
type drugs. 125, 126, 127, 128 Post-synaptic agonism may well imply some kind of
reciprocal relationship with serotonin 2,implying again a serotonin 2 antagonism,using a variety of models,namely model of hypo/hyperthermia,hypotension / hypertension 129,quipazine
related effects,habituation of
tactile startle via actions at 5-HT2 receptors 125,
130, 131and
evenmigraine132.

A
wide variety of human psychopathologies reflecting serotonin 1A involvement
can therefore be analyzed in detail,particularly so as buspirone is
safe,used extensively in clinical
practice and in low doses non-sedative. It haslow toxicity,few side-effects,no established lethality (LD 50 that has
not even been established in man),very little cognitive and psychomotor impairment. and
no apparent potential for dependence.Buspirone despite its anxioselective action does not act on
benzodiazepine or GABA receptors. Many typical anxiolytic drugs like the
benzodiazepines which induce sedation,muscle relaxation,anticonvulsant effects,act almost immediately and may induce
dependence. 19, 20

This azapirone’s action appears
to be broad,so
that the phrase "anxioselective neuromodulator" can be used. 19 Buspirone has a short half-life,requiring thrice daily
dosing,and has limited interactions
with other drugs. 19 It has been used with
several hundred other psychotropic and other compounds without major
interactions. 133, 134 Its major metabolite (like gepirone and
tandospirone) is 1-2 pyrimidinyl piperazine or 1PP. 135,
136, 137, 138, 139 There is some dispute as to the level of activity
of 1PP,which
occurs in significant amounts. 138, 140, 141

There is substantial animal evidence for buspirone
being a potent anti-aggressive substance,and this applies to other
azapirones such as gepirone and ipsapirone38, 45, 142, 143 as well.This anti-aggressive effect should be at the serotonin 1A receptor,
and this in fact may be one of the fundamental actions at this level. 20, 68] In fact,using every single animal model for aggression,relating to muricidal behavior and
conflict-related aggression,inter-species and intra-species related aggression,isolation-induced modelsand group-related models,buspirone comes out as a very potent
anti-aggressive agent in appropriate doses,and this property appears shared by gepirone. 45, 115, 144In the
muricidal model,buspirone requires higher doses,not having effects in lower doses45: it
potently inhibited attacks against group housed intruder mice (ED50 =
4.5 mg/kg i.p.) without causing
sedation or ataxia. Inhibition of aggression was
potentiated by co-administration of methysergide. 45This is
particularly so as many of the paradigms used in animals to demonstrate the
anxiolytic effect of buspirone can be also used to
demonstrate its anti-aggressive effect. 68 Theoretically,supporting models exist in man. 145

However,double blind
studies in aggression in man are lacking. Irritability is an early target
symptom of response with buspirone in generalized anxiety disorder possibly
implying persistent low-doseeffects. 146, 147, 19.Also,Ratey has published
his uncontrolled data,on 14 mental retardates,nine of whom responded favorably to the drug. 148, 149.Numerous other case reports are scattered in a
variety of different uses. 150, 151, 152, 153, 154,
155, 156, 157A small
amount of irritability ranking data exists in a double-blind study on
pre-menstrual syndrome 151, 158, 159, 160, 161, 162159, 161. In all studies
buspirone was very promising. Possible applications of aggression,research in
man,relate to psychogeriatric
patients 20], 163, 164, 165 the personality disordered people and people with
frustration leading to aggression. 125

OUR STUDIES

I
will also now contribute our small open pilot data in this regard using
several cohorts. The data is preliminary with the typical limitations of
real clinical patients. It should consequently be interpreted
with caution. However,several new elements are important involving buspirone
applications in the this out-of-labeling context.

1.
use in a non-organic sample in low
doses(Cohort 1 and part of
Cohort 3)

2.
use in a manic-like sample (Cohort 2) and mania and other conditions (part
of Cohort 3) in high dosessuggesting bimodal dosage

3.
use in a temporal lobe dysfunction subgroup with carbamazepine.(Cohort 4)

None
of these cohorts overlap

Sample

We
evaluated the efficacy of buspirone in the management of in - and out-
patients referred with main complaints of orwith major problems of aggression.
Our study involved an open trial of buspirone to inpatients or outpatients
referred for a variety of reasons,but with a very major part of
their presentation being aggression,irritability or violence as main complaints. These patients
generally had little or no clinically significant anxiety (to distinguish
the anxiety component of treatment).Because buspirone is marketed for generalized anxiety disorder (GAD)
and this condition frequently has frustration and consequent irritability,we excluded all
patients specifically labeled as having GAD to definitely separate the two
conditions.We included all
successive referrals with aggression who had been
placed onto buspirone. We also included a small subpopulation of patients
going into or coming out of a manic episode who were irritable.

Cohort 1 :Short -term inpatients on low dose
buspirone

These
patients were given low dosesof buspirone,generally of the order of 15-25 mg per
day.Our cohort is of nine such
successive inpatients. Several of these were intractable and varied from
being on no ancillary medication to other medications,for example carbamazepine or
fluoxetine. This study evaluated only short-term improvements for practical
reasons:changes at the end of
hospitalization or first follow-up.At the dose given (15mg to 25mg per day),all 9 subjects ( mean age : 29±11 years ;
8 males ) exhibited some improvement both globally using clinical global
assessments of change,and also
specifically on hostility rankings based on a 0-6 ordinal ranking of the
Kay criteria for the Brief Psychiatric Rating Scale (BPRS) (Table 1).The improvements ranged from slight in
one (the female ),moderate in two,and
substantial in the rest. Using the ordinal scale of range 1{slight} through
6 {very marked},themode was 4,and the median was 3.Using abinomial ranking of improved vs
not improved,these results are
significant at the p<0.001
level. Response generally took about 4-5 days to be most overt although
patients continued to note greater improvements.The biggest difficulty is interpreting
the data clinically in the absence of controls - many inpatients improve with
milieu and re-evaluating these patients retrospectively,we could have predicted that as many as
five of the nine would have improved without the buspirone intervention.
Because of this the Clinical Global Impressions Rankings (CGI) were useful : the patients were generally severely ill
initially and exhibited rankings of clinically relevant improvement on
overall therapeutic efficacy with low side-effects and excellent efficacy
index. (Table 1 )

We
have examined another cohort of twelve patients both inpatient and
outpatient who have been receiving high doses of buspirone,approximately 60-160 mg per day of
buspirone,for profound irritability
linked with a manic like state. This group had associated marked agitation,restlessness,anger,lability of mood and confrontation with enormous potential for
tolerating high doses of medication. These patients were all exceptional:
they were not typical manics who would respond to lithium,carbamazepine or valproate alone
or combinations of these.Buspirone
was initiated outside labeling but on solid clinical grounds where lithium or neuroleptics or benzodiazepines were
contraindicated or where we did not want to escalate the doses of these drugs.Sometimes buspirone treatment was
initiated coming out of the manic phase: for example,when a patient had been lithium
toxic and we did not want sedation. At times patients received the
buspirone early in the manic like phase - for example,a patient with AIDS involving the
brain and ostensible organic brain disorder associated with manic features.
Others received it during their manic episode:these patients had sometimes been
routinely sedated,with neuroleptics and/ or with benzodiazepines, but for clinical reasons,we did not want to continue the
sedation.As the mania began to
improve a little,they remained extraordinarily irritable,angry and hostile,pacing and agitated.

All
patients were generally begun directly on 60 mg of buspirone a day,20 mg t.i.d.
All twelve improved on short-term follow up over days,generally markedly.Improvements were noted
within twelve to 24 hours. The agitation and confrontation would improve
markedly,however,the psychotic features still required
antipsychotics.Frequently,the patients
would report remarkable improvement in their sleep on the first night but
this was not maintained and would require other interventions.Often,within a day or two,they would complain of a tell-tale “non-vertiginous
dizziness” which we used as a criterion for lowering dosage as they were no
longer tolerating the higher dose.Some patients therefore received high dose buspirone for days and
then required tapering generally when they became dizzy. The endpoint was
frequently low dose buspirone -15mg per day.At least 3 patients,on whom follow-up occurred within
the system,were still taking
buspirone in doses of 60mg per day or above several years later. With three
exceptions of buspirone monotherapy,these patients were on other
therapies as well- lithium,valproate,carbamazepine,benzodiazepines,antidepressants and/ or neuroleptics.

As illustrations,our first two
cases had two similarities.In each
instance,these
patients had been ill for many years and constituted the far end of
severity for bipolar illness with chronic intractability. The families did
not know what medications the patients had been on and in fact in each case,they had
encountered some difficulties with the patients' initial conditions.
Spontaneously,they both commented they had never seen these members of
family so well,after a manic
episode. Of the first twelve patients,four families have reported this amazement with response compared
with previous episodes describing how the index patients were
greatly improved on the high dose buspirone.

We have seen three cases in
which 60mg ofbuspirone daily apparently markedly attenuated episodes of
both depression and mania in patients who prior to that were intractably
cycling despite the best known previous interventions including drugs such
as lithium,carbamazepine,valproate,antidepressants and neuroleptics in
varying combinations.In one case the patient was controlled except for minor mood
changes for three yearsShe then
went off the buspirone herself and relapsed.Could this imply a prophylactic effect of
the drug in certain refractory bipolar illnesses,particularly as their may be a
pharmacologic justification - lithium has an effect on serotonin 1A? Clearly,this should be explored further -
it may be that buspirone has prophylactic effects on bipolar disorder.

Cohort 3 :Outpatients with buspirone for
irritability

In
conjunction with John Walenta (who analyzed data retrospectively),we have followed
at the Pacific Neuropsychiatric Institute a group of adult non-organic
patients (children are discussed separately 166 ) treated with buspirone for aggression.These patients had consented to allow
their clinical data to be analyzed.Follow ups were done based on their
short-term response to buspirone (criterion :
their first two appointments after initiating buspirone,up to one month after start) and their
last appointment ( very often current) while on buspirone.Their condition was ranked based on
retrospective chart review using a five point ordinal scale ( 2 being very much improved,0 being no change or equalfeatures worse and better,and -2 being very much worse). The
results are dramatic with 12 of 13of patients improving.Low dose response(15-25mg per day ) as well as high
dose response was excellent (≥ 50mg per day).(Table 5).Our experience has been that patients do better on lower doses of
buspirone than mid-doses with regard to aggressionbut their anxiety and depression
respond better at 30mg to 45 mg per day than 15mg per day.

A
prototype example is of a patientin his mid-thirties who was
having,on average,four to five episodes a dayof extreme aggression and anger which he
found very difficult to control.The
major precipitant was when vehicles would overtake him on the road,and as he was a
builder,he was involved in such
episodes about three times per day as he drove several times per day. I
have called this condition the WestCoastSyndrome.The patient
charted his baseline episodes and then began on buspirone in doses of 15 mg
per day.In the first week he had
had two such episodes,and then it dropped down to zero as the dose increased
through 20 and 25 mg per day.However,by
the time he achieved 30 mg per day,he was recording again two episodes per week with equivalent
stressors.We dropped him back and
he has been stabilized now for several years on 15
mg per day.Follow-up is now the
longest of any patient we have treated- nearly 6 years on buspirone.He's having no episodes of marked
pathologic aggression,and this is not only in the motoring context. His wife,who had wanted
to divorce him because she could not tolerate these,reports an enormous improvement as well.
He irregularly becomes frustrated but well within normal range.He at one point,went off the buspirone and was in
remission for about a month,and
then his symptoms began to return.Re-initiation of the drug produced the same dramatic improvement. This
is the typical kind of case of a patient who does better on lower doses
compared with higher doses of buspirone.

Table 2 : regular adults on
buspirone for aggression

N=13

9M, 4F

Age

Frequency of dosing

Dose in mg

Other

medics

Months on buspirone

Early

Response

Later Behavioral Response

Later

Subjective

Response

mean

39.5

3.1

33.1

1.31

19.5

1.67

1.41

.67

SD

19.4

0.28

25.9

1.18

14.33

0.49

1.31

.63

median

37

3

15

1

18

2

2

1

mode

19

3

15

2

2

2

2

0

range

17 to 78

Cohort 4 :Buspirone and carbamazepine combination :
special cases

Drugs
such as carbamazepine have enormous potential in the management of episodic
disorders particularly those linked with hostility. 167, 168, 169,
170, 171, 172. A subpopulation of patient exhibits
features of a special kind of aggression which is
carbamazepine responsive and appears to not respond to buspirone
alone.These patients have special
episodes with explosive,uncontrolled,poorly
directed,limited precipitation kind
of aggression with or without amnesia.These kinds of episodes on their own theoretically should not
respond to buspirone as they are probably not modulated through serotonin
1A but through episodic firing in the brain,possibly the temporal lobes.

These
patients commonly have temporolimbic instability. This diagnosis is based
on three key elements:

1.
History using subjective report measures such as the Inventory of Neppe of
Symptoms of Epilepsy and the Temporal Lobe {INSET }where
they have several symptoms 173 .

2.
Examination including neurologic evaluation is often normal although higher
brain function based on measures such as the BROCAS SCAN (Screening
Cerebral Assessment of Neppe) 174 sometimes suggests compromise of frontal or
parietal lobes and soft neurologic features.

Many
patients in this major subgroup have coarse neurobehavioral symptoms for
which carbamazepine not buspirone is prescribed, 180,
181 possibly qualify for diagnoses of intermittent
explosive disorder,but are more
correctly labeled paroxysmal neurobehavioral disorder * and are
carbamazepine responsive. They do not require adjunctive buspirone. A
special group,however,do :

These
patients frequently have added frustration and irritability and build up of
distress which they can control. The carbamazepine
alone does not seem to help these features,but the buspirone does.
Consequently,we
have a cohort of patients on the combination of carbamazepine (always as
Tegretol generally 600mg per day or titrated to serum levels of about 6-9
ug per liter) and buspirone (variably low dose or high dose).These patients have responded well
subjectively to the combination in 10 out of 12 cases (and behaviorally in
11 or 12)continuing the treatment. However,8 patients discontinued on the CBZ
so the overall combination responsiveness was 10 out of 20 although all 8
dropouts improved on the buspirone.Of the20
patients,2 were on carbamazepine
for classical seizure phenomena with loss of consciousness not
dyscontrol,and 9 others exhibited
no dyscontrol features and were on the carbamazepine for other reasons -
temporal lobe symptomatology or affective illness. It is relevant to
mention that in no instances did buspirone directly impact on dyscontrol
behavior when present,however,in the 18 of 20instances where buspirone helped the
irritability-frustration continuum,our impression was that the patients would report less dyscontrol
when present,but we have not
specifically kept such data.In 3
cases,the
carbamazepinewas initiated
first,and because of the distortion
of this sample,by definition,none responded dramatically otherwise
this would not be necessitating the buspirone. Once the combination was
used but 12 improved and 8 remained the same or deteriorated requiring
discontinuation of the carbamazepine ( 5 of them
took other anticonvulsants instead of carbamazepine and of these 4 have
remained on either valproate or phenytoin. ). Longest follow-up has been
four and a half years on the combination. (Table 4 reflects months on
buspirone).

Table 3: Buspirone and carbamazepine
combination

N=14;

10M,4F

Age

Frequency of dosing

Dose in mg

Other

medics*

Months on buspirone

Early

Response

Later Behavioral Response

Later

Subjective

Response

mean

33.7

3

47.9

2.71

22.43

1.86

1.85

1.53

SD

14.3

0.39

37.3

1.59

14.22

0.36

.67

.77

median

34

3

30

2.5

22.5

2

2

2

mode

-

3

75

4

32

2

2

2

range

12 to 57

*
this refers to other prescription medications besides the buspirone taking
concomitantly

Table 4: Carbamazepine dropouts on
buspirone

N=8

4M,4F

Age

Frequency of dosing

Dose in mg

Other

medics

Months on buspirone

Early

Response

Later Behavioral Response

Later

Subjective

Response

mean

43.8

3

36.3

1.88

19.5

.75

1.58

1.58

SD

13.5

0

23

0.84

14.33

0.89

0.53

0.53

median

42.5

3

32.5

2

18

1

2

2

mode

-

3

15

1

2

1

2

2

range

26 to 65

Table 5
:Outpatient responsive to buspirone
based on dosage

Buspirone

10-25mg/dbus

30-55mg/day

60-140mg/day

^^

SIZE

response

SIZE

response

SIZE

response

Cohort 3

9

9

0

0

4

3

CBZ+ BSP

5

5

3

3

4

3 (2 subjectively)

CBZ dropouts

4

4

0

0

4

4

# RESPOND^

18

3

10 (9 subjectively)

TOTALS

18

3

12

^ responses based on yes or no for early and late
patients identical except one less patientin CBZ+ BSP group assessed (new patient) in the late group and one
less in high dose CBZ+BSP group (Cohort 4A) subjectively responded

^^ a patient with aggression on 140mg / day for
tardive dyskinesia

Discussion

Our
results are remarkable for how well patients seem to have done. These
results arehighly
preliminary although highly statistically significant because of the global
response.However,this wasnot unexpected given the special
selection of the population. The sample of patients that
present in an academic setting is specialized and does not reflect the
general population. In addition,in the inpatients,their status in hospital compromised interpretation
of the improvement as milieu or removal away from the stressors may have
been the explanation. Moreover,our outpatientswere frequently highly motivated to get
better. In addition,these patients were very complex and they were often
veryill at presentation,implying they had significant room to
improve particularly in an environment where each patient was intensely
evaluated and medication was very carefully chosen and adjusted for best
fit at follow up.Additionally,in general,their conditions necessitated
polypharmacy (Tables 2, 3 and 4). The object was to help the patients and
it is impossible to assess the contribution of each drug or the environment
or therapeutic milieu. Many,if not most patients given these
criteria,will improve - and the
particular sample is further distorted by those who chose to
follow-up.In eleven cases,the patients
are not being followed up by us at this point ( six for geographic reasons
or 4 because their primary physicians have taken them over and because she
is subjectively so improved she deems it unnecessary. However,in reality,several of these patients may in
fact,have not followed up with us
because they are not doing well which further distorts the positive results
which technically is overwhelmingly statistically significant for
improvement (vs not improved ) as a group and also significant in each
individual group.These factors
emphasize the need for controlled prospective studies and the limitations
of clinical data. Besides the above,the operational criteria for entry
into the analysis namely aggression,irritability and violence are suspect because they have been lumped
together. Finally,the methods of ranking are suspect because in general they
were too global,and although based
on detailed chart review a five point ordinal scoring of change either
globally or on one criterion - aggression is simplistic and even
inappropriate.On the other hand,the results in
4 different cohorts are consistent and encourage hypothesis testing.
Nevertheless,thecomments below should be perceived
with a full realization of the inadequacies of this research.

If the results can be replicated
and are real,these open pilot studies suggest that there may be two
subpopulations of patient responsive to buspirone for aggression,irritability and impulsivity.Preliminarily,based on our experience,low dose buspirone therapy (10-25 mg per
day usually) produces responsiveness in non-organic patients with high
levels of frustration and /orhigh
stress levels who have significant chronic irritability and impulsive
directed acting out behavior with a range through from verbal to physical
aggression.High doses of buspirone,generally
60-90mg per day,appear to act
within hours,not within the days
that low doses require,and to be
associated with alleviation of the high level irritability and agitation of
patients who are hypomanic and confronting.Very preliminarily and based on only limited clinical
experience,high doses also might be
logical when there has been limited low dose response,or when other diagnoses requiring higher
doses of buspirone are present such as obsessive compulsive disorder or the
marked agitation of the severe Alzheimer patient.

In thetwo very preliminary open studies in
which low doses such as 10-25 mg per day of buspirone appear to be very
effective anti-aggressive agents in two different population cohorts,namely,mentally-retarded,brain-damaged,aggressive
patients 148, 149,and my
own study (Cohorts 1-4) with predominantly non-organic aggressive patients 182, 183 who did not have generalized anxiety disorder
superimposed,as the dose increased
to about 30mg per day,the
anti-aggressive effects waned,although there remained some residual effect. This low dose
effect may correspond with a presynaptic autoreceptor serotonin 1A agonist
firing with consequent diminished postsynaptic tone across all serotonin
receptors. These presynaptic results are to some degree contradicted by our
ADHD and aggression studies in children described in this issue and usually
involving doses of 30mg per day of buspirone. 166

Our results suggest two
potentially different mechanisms for the management of aggression using
buspirone: Low doses may correspond with a presynaptic agonism with a
feedback loop producing overall postsynaptic antagonism at all serotonin
receptors. This would imply a short delay,such as days,which is what one finds. Conversely,high
dosage,postsynaptic agonism in the
irritable hyperactive agitated kind of patient would imply a secondary
regulation of the serotonin 2A receptor,with consequent serotonin 2 antagonism : this may characterize an
intimate,inverse feedback relationship
with serotonin 2 mechanisms. It may alternatively reflect receptor
subsensitivity in manic and related psychotic or agitated states implying
higher doses.

Appropriate dosage of
buspirone is critical to success.I
believe that one useful way to modulate the dose is based on the side-effect of dizziness. The dizziness that occurs with
buspirone is special and Neppehas used the term “non-vertiginous
dizziness” (NVD) for it. 20 This dizziness is by far the most common side effectin
adults,possibly occurring in 30-40%
of patients but when the dose is built up to 60mg per day in possibly 60%
based on my guesstimate on hundreds of my own patients.It apparently can be
used as an index of what dosage of buspirone we ought to be able to
achieve. Increasing the dosage is often critical management so that this
side-effect can be used to monitor dosage exemplified by the
following:A patient started on 5
mgs of buspirone 3 times a day,and instead of improving,the patient reported a few days
later,"Aboutthirty minutes after I take the
drug,I get this horrible sensation
in my head.It's a dizziness,it's an uncomfortability,it's a light headedness,it's indescribable.It goes behind my ears and I don't like it. It lasts about 30 minutes and then it
goes away.”The same scenario might occur while
building up the dose at (say) 40 mgs a day.In every instance when one gets this,we believe this is as much asymptom of serotonin 1A responsiveness as
isirritability and concentration.It is a direct serotonin 1A related side
effect.It apparently occurs with
other azapironesin research and also,in may experience,occurs
occasionally,for example,with the other serotonin 1A non specific
drugs such as lithium and propranolol.When this side effect occurs,this may be hypothesized to be a symptom of serotonin 1A
overmodulation or excess and I find that dropping down the dosage of buspirone
is all that is needed (e.g.if 15 mgs a day produces NVD,drop to 10 mg per day.If the patient isstill getting “non-vertiginous
dizziness”,drop to 5 mgs a day -
2.5 mg bid- until the
“non-vertiginous dizziness” disappears: this should be the correct dosing.Using this technique,far fewer patients in my experience,drop-out and also far more patients
appear stabilized.

An integrated model

The
perspective of dose dependency appears extremely important,not only on the
basis of side effects but also therapeutic effects.This is illustrated by comparing effects
of specific versus nonspecific serotonin 1A modulators wheredifferent effects speculatively
occur at different levels. The consistency of the chemistry,the
receptorology,animal models and
clinical implications may provide a viable approach to examining this and
other receptors during the 1990's.

A model for aggression can be drawn
using the serotonin 1A receptor.Presynaptic agonism produces a functional overall post-synaptic
antagonism,and
this could be the mechanism for low-dose buspirone in the agitated,generally non-organically impaired
angry,frustrated,hostile,irritable individual.High
doses of serotonin 1A agonist in the context of high doses of buspirone,or of
lithium,produces post-synaptic
serotonin 2 antagonism as a reciprocal effect for the serotonin 1A agonist
effect.Beta adrenergic blocking
agents in low doses probably do not act by the serotonin 1A receptor,but in higher
doses act as serotonin 1A antagonists and also serotonin 1B agonist type
drugs.Under those circumstances,if serotonin 1B
indeed does exist in man,this would
explain the paradoxical effect. However,the high dose serotonin 1A agonist
theory appears compromised unless the serotonin 1B agonist effects that
propranolol exhibits in rodents can be translated into equivalent,currently undiscovered human effects.
This is unlikely at this point and a more logical hypothesis for
beta-blockers could relate to down regulation of the serotonin 2 receptors which may produce the equivalent of serotonin
2 blockade. As an aside, because gepirone potently inhibits serotonergic
impulse flow recorded from the dorsal raphe nucleus and this effect is
partially reversed by serotonergic antagonists, this presynaptic effect may
be its primary effectdecreasing 5HT neurotransmission. 45Thus,theoretically,gepirone may turn out even better than
buspirone as an anti-aggressive agent .

Neurochemically,a very
important theoretical and practical area in relation to serotonin and
serotonin 1A has emerged.It has
implications far beyond serotonin 1A,as a cascade of mechanisms across
many chemical levels can occur.For
example,the
possibility of some degree of inverse relationship with serotonin 2
mechanisms is only a beginning and influence in relation to electrical
firing at dopaminergic,acetylcholine and norepinephric levels occur.The exact effects will vary depending on
the particular parent compound.

The time has arrived for the
azapirones to be thoroughly investigated and possibly to be marketed
thereafter as the first anti-aggressive agents without sedation,addiction and
neuroleptic effects and with significant safety.

83.Goodwin
GM, De Souza RJ, Wood AJ, Green AR : The
enhancement by lithium of the 5-HT1A mediated serotonin syndrome produced
by 8-OH-DPAT in the rat: evidence for a post-synaptic mechanism.Psychopharmacology (Berlin)90 (4):488-93, 1986

182.Neppe VM. Perspectives on the pharmacologic management of agitation and
irritability in the geriatric patient. In:Psychiatric Disorders in the Elderly:
Current Treatment Practices, Conference ed. San Francisco: Mt Zion
Institute on Aging,56-62, 1993